chr4-106235347-GT-G
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001163435.3(TBCK):c.1370delA(p.Asn457ThrfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,454,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
TBCK
NM_001163435.3 frameshift
NM_001163435.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.75
Publications
9 publications found
Genes affected
TBCK (HGNC:28261): (TBC1 domain containing kinase) This gene encodes a protein that contains a protein kinase domain, a Rhodanase-like domain and the Tre-2/Bub2/Cdc16 (TBC) domain. The encoded protein is thought to play a role in actin organization, cell growth and cell proliferation by regulating the mammalian target of the rapamycin (mTOR) signaling pathway. This protein may also be involved in the transcriptional regulation of the components of the mTOR complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]
TBCK Gene-Disease associations (from GenCC):
- hypotonia, infantile, with psychomotor retardation and characteristic facies 3Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
- syndromic complex neurodevelopmental disorderInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-106235347-GT-G is Pathogenic according to our data. Variant chr4-106235347-GT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 225241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001163435.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TBCK | MANE Select | c.1370delA | p.Asn457ThrfsTer15 | frameshift | Exon 15 of 26 | NP_001156907.2 | Q8TEA7-1 | ||
| TBCK | c.1370delA | p.Asn457ThrfsTer15 | frameshift | Exon 15 of 26 | NP_001156908.2 | Q8TEA7-1 | |||
| TBCK | c.1253delA | p.Asn418ThrfsTer15 | frameshift | Exon 15 of 26 | NP_001156909.2 | Q8TEA7-2 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TBCK | TSL:1 MANE Select | c.1370delA | p.Asn457ThrfsTer15 | frameshift | Exon 15 of 26 | ENSP00000378198.2 | Q8TEA7-1 | ||
| TBCK | TSL:1 | c.1253delA | p.Asn418ThrfsTer15 | frameshift | Exon 15 of 26 | ENSP00000378196.3 | Q8TEA7-2 | ||
| TBCK | TSL:1 | c.1181delA | p.Asn394ThrfsTer15 | frameshift | Exon 13 of 24 | ENSP00000355338.4 | Q8TEA7-3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1454874Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 723748 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
2
AN:
1454874
Hom.:
Cov.:
30
AF XY:
AC XY:
1
AN XY:
723748
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
1
AN:
33208
American (AMR)
AF:
AC:
1
AN:
44236
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25898
East Asian (EAS)
AF:
AC:
0
AN:
39342
South Asian (SAS)
AF:
AC:
0
AN:
85534
European-Finnish (FIN)
AF:
AC:
0
AN:
52424
Middle Eastern (MID)
AF:
AC:
0
AN:
5734
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1108482
Other (OTH)
AF:
AC:
0
AN:
60016
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
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0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
4
-
-
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (4)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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